rs2076349

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000228.3(LAMB3):c.1579G>A(p.Val527Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0695 in 1,613,446 control chromosomes in the GnomAD database, including 14,383 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.13 ( 2724 hom., cov: 33)

Exomes 𝑓: 0.063 ( 11659 hom. )

Consequence

LAMB3
NM_000228.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.601

Publications

30 publications found

Variant links:

Genes affected

LAMB3 (HGNC:6490): (laminin subunit beta 3) The product encoded by this gene is a laminin that belongs to a family of basement membrane proteins. This protein is a beta subunit laminin, which together with an alpha and a gamma subunit, forms laminin-5. Mutations in this gene cause epidermolysis bullosa junctional Herlitz type, and generalized atrophic benign epidermolysis bullosa, diseases that are characterized by blistering of the skin. Multiple alternatively spliced transcript variants that encode the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

LAMB3 Gene-Disease associations (from GenCC):

junctional epidermolysis bullosa
Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
junctional epidermolysis bullosa Herlitz type
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, Laboratory for Molecular Medicine
junctional epidermolysis bullosa, non-Herlitz type
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Genomics England PanelApp, Ambry Genetics
amelogenesis imperfecta type 1A
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
amelogenesis imperfecta type 1
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
generalized junctional epidermolysis bullosa non-Herlitz type
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LAMB3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.3354112E-5).

BP6

Variant 1-209626885-C-T is Benign according to our data. Variant chr1-209626885-C-T is described in ClinVar as Benign. ClinVar VariationId is 255586.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.555 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAMB3	NM_000228.3 link	c.1579G>A	p.Val527Met	missense_variant	Exon 13 of 23	ENST00000356082.9	NP_000219.2	Q13751A0A0S2Z3R6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LAMB3	ENST00000356082.9 link	c.1579G>A	p.Val527Met	missense_variant	Exon 13 of 23	1	NM_000228.3	ENSP00000348384.3	Q13751
LAMB3	ENST00000367030.7 link	c.1579G>A	p.Val527Met	missense_variant	Exon 13 of 23	1		ENSP00000355997.3	Q13751
LAMB3	ENST00000391911.5 link	c.1579G>A	p.Val527Met	missense_variant	Exon 12 of 22	1		ENSP00000375778.1	Q13751

Frequencies

GnomAD3 genomes

AF:

0.130

AC:

19792

AN:

152182

Hom.:

2710

Cov.:

show subpopulations

Gnomad AFR

AF:

0.267

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.184

Gnomad ASJ

AF:

0.0167

Gnomad EAS

AF:

0.572

Gnomad SAS

AF:

0.118

Gnomad FIN

AF:

0.0165

Gnomad MID

AF:

0.0665

Gnomad NFE

AF:

0.0277

Gnomad OTH

AF:

0.117

GnomAD2 exomes

AF:

0.132

AC:

32973

AN:

250462

AF XY:

0.118

show subpopulations

Gnomad AFR exome

AF:

0.274

Gnomad AMR exome

AF:

0.300

Gnomad ASJ exome

AF:

0.0196

Gnomad EAS exome

AF:

0.581

Gnomad FIN exome

AF:

0.0203

Gnomad NFE exome

AF:

0.0271

Gnomad OTH exome

AF:

0.0888

GnomAD4 exome

AF:

0.0632

AC:

92355

AN:

1461146

Hom.:

11659

Cov.:

AF XY:

0.0627

AC XY:

45604

AN XY:

726892

show subpopulations

African (AFR)

AF:

0.285

AC:

9527

AN:

33452

American (AMR)

AF:

0.289

AC:

12920

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.0183

AC:

479

AN:

26130

East Asian (EAS)

AF:

0.577

AC:

22894

AN:

39672

South Asian (SAS)

AF:

0.110

AC:

9463

AN:

86216

European-Finnish (FIN)

AF:

0.0208

AC:

1105

AN:

53164

Middle Eastern (MID)

AF:

0.0739

AC:

426

AN:

5766

European-Non Finnish (NFE)

AF:

0.0271

AC:

30178

AN:

1111684

Other (OTH)

AF:

0.0888

AC:

5363

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

4308

8616

12924

17232

21540

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1708

3416

5124

6832

8540

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.130

AC:

19855

AN:

152300

Hom.:

2724

Cov.:

AF XY:

0.132

AC XY:

9830

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.267

AC:

11099

AN:

41560

American (AMR)

AF:

0.185

AC:

2832

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0167

AC:

AN:

3472

East Asian (EAS)

AF:

0.572

AC:

2956

AN:

5166

South Asian (SAS)

AF:

0.118

AC:

570

AN:

4824

European-Finnish (FIN)

AF:

0.0165

AC:

175

AN:

10630

Middle Eastern (MID)

AF:

0.0748

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0277

AC:

1885

AN:

68026

Other (OTH)

AF:

0.120

AC:

254

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

777

1554

2332

3109

3886

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

204

408

612

816

1020

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0786

Hom.:

4326

Bravo

AF:

0.155

TwinsUK

AF:

0.0213

AC:

ALSPAC

AF:

0.0291

AC:

112

ESP6500AA

AF:

0.254

AC:

1119

ESP6500EA

AF:

0.0271

AC:

233

ExAC

AF:

0.125

AC:

15136

Asia WGS

AF:

0.308

AC:

1073

AN:

3478

EpiCase

AF:

0.0297

EpiControl

AF:

0.0263

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Junctional epidermolysis bullosa, non-Herlitz type

Benign:1

Jul 08, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Amelogenesis imperfecta type 1A

Benign:1

Jul 08, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Junctional epidermolysis bullosa gravis of Herlitz

Benign:1

Jul 08, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Junctional epidermolysis bullosa

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.73

CADD

Benign

9.7

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.060

T;T;T

Eigen

Benign

-0.86

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.056

LIST_S2

Benign

0.053

.;T;.

MetaRNN

Benign

0.000013

T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Uncertain

2.0

M;M;M

PhyloP100

-0.60

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.45

N;N;N

REVEL

Benign

0.035

Sift

Benign

0.068

T;T;T

Sift4G

Benign

0.074

T;T;T

Polyphen

0.60

P;P;P

Vest4

0.023

MPC

0.13

ClinPred

0.0076

GERP RS

-2.5

Varity_R

0.074

gMVP

0.24

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over